Sometimes the drug comes first

Beginning in 2000, the FDA approved four drugs to treat premenstrual dysphoric disorder, a more severe form of PMS.

The hitch: The condition didn't yet exist.

The FDA approvals started less than 2 years after a private meeting of six FDA officials with four executives from Eli Lilly. The drug company's patent on the antidepressant Prozac (fluoxetine) was about to expire and officials had a new market in mind.

That gathering of 10 took place in Washington, DC and was part of a Lilly-sponsored meeting that included 16 researchers interested in PMDD.

At the time, there was strong disagreement about the condition, which had been listed as being in need of further study by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders (DSM).

That didn't stop the meeting participants.

On their own, they determined PMDD was a distinct clinical disorder and declared that selective serotonin reuptake inhibitors (SSRIs) such as Prozac were effective at treating it.

For the PMDD version of the antidepressant, Eli Lilly changed its green-and-yellow capsule to pink-and-purple, and gave the drug a more feminine-sounding name: Sarafem.

Sarafem won FDA approval and then it approved three drugs from other companies: the antidepressants Zoloft (sertraline) in 2002 and Paxil (paroxetine) in 2003, followed by the birth control pill Yaz (drospirenone/ethinyl estradiol) in 2006.

But those approvals all pre-dated the 2013 decision of the American Psychiatric Association to recognize PMDD as a distinct psychiatric condition -- a determination based on the recommendation of a panel on which nearly 70% of the members had drug company ties.

By then, marketing had created demand: For instance, annual sales of Yaz peaked at $782 million in 2009, though sales dropped after that year following reports linking drugs in its class with dangerous blood clots.

The market was built on a disputed condition, inflated estimates of how many women have it, and drugs that can carry severe risks, such as suicidal thinking in the case of antidepressants.

Conclusions from that 1998 meeting were presented as a consensus, but one participant whose name appears on the paper said she never agreed that PMDD was a mental condition or that antidepressants should be used to treat it.

To this day, Sally Severino, MD, an emeritus professor of psychiatry at the University of New Mexico, said she holds an opposite view. She said in an interview there never has been convincing evidence to prove either contention.

She also offered an explanation about why the 1998 meeting was called.

"We were on the road to making this a mood disorder," she said. "I think the pharmaceuticals had a lot of influence."

Marketing or Medicine?

Like other everyday conditions that in recent years have morphed into mainstream disorders treated by expensive and often dangerous drugs, a MedPage Today/Milwaukee Journal Sentinel investigation into PMDD found evidence of drug company influence -- and money -- at virtually every step along the way.

What stands out about PMDD is that so much of the effort began long before it was recognized as a psychiatric disorder.

Start with that 1998 meeting, paid for by Lilly.

On its face, the meeting -- which over the years has received scant public attention -- was unusual.

"For the FDA to participate in this behind closed doors is very troubling," said Michael Carome, MD, director of the health research group of Public Citizen, a watchdog organization that is a frequent critic of the pharmaceutical industry and the FDA. "It had a direct outcome on their (Lilly's) financial bottom line."

Lilly spokesperson J. Scott MacGregor said a check of company records show the meeting was called after Lilly met with FDA officials "who suggested it would be useful" to convene experts to determine if PMDD was a distinct disorder.

In an email, FDA spokesperson Lauren Shaham defended the agency's participation in the meeting and noted that a public discussion of the condition was held about a year later at the FDA advisory committee meeting that reviewed the Sarafem new drug application.

"FDA staff often participate in various external meetings with the drug development, physician, academic, and patient communities in many disease areas," she said.

Critics also say it is unusual for a group of doctors to independently determine what is or is not a medical or psychiatric condition. That typically falls to medical societies or associations.

A leader of the 1998 meeting and the lead author on the subsequent paper was Jean Endicott, PhD, a psychologist at Columbia University. Endicott has had longstanding financial ties to companies that manufacture drugs for PMDD, including Eli Lilly, GlaxoSmithKline, and Pfizer.

In the paper, published in the Journal of Women's Health, the researchers said they looked at evidence such as published studies and listened to individual presentations. They also considered "perceptions" about the condition.

When the FDA advisory committee meeting was held 5 months later, the results of the paper were not presented by Endicott or any co-authors. Instead, a transcript of the meeting shows, results were handled by a doctor from the Society of Women's Health Research -- the group that convened the meeting after getting money from Lilly to pay for it.

But Endicott was in attendance, this time testifying on behalf of Lilly.

According to the transcript, one of the FDA panel members asked: Why was PMDD not recognized by the psychiatric community?

Endicott chalked it up to internal politics.

"There were other issues going on, and this is always a committee kind of decision in a general setting in which political issues do get considered," she said.

After unanimous support from the advisory committee, the FDA approved the drug.

Allen Frances, MD, chairman of an APA panel that in 1994 had decided not to elevate PMDD to an official condition, said he was "puzzled" at the time about the approval. The condition, he said, "wasn't ready for prime time."

In an interview, he said it was "absolutely absurd for the FDA, in secret meetings with drug companies, to make a decision that would be contrary" to what the psychiatric community had decided about PMDD at the time.

"That's not the way regulators are supposed to work," he said. "It's the fox guarding the hen house."

Similarly, treatment guidelines to help doctors decide how to treat PMDD were issued before the condition was recognized as an official psychiatric disorder.

Typically such guidelines, which can be influential, are issued by medical societies or other groups. In this case, the 2006 guidelines were issued by a small group of researchers and were paid for by GlaxoSmithKline -- the maker of Paxil.

The guidelines proclaimed antidepressants "the treatment of choice" for PMDD.

The guidelines were published in the Journal of Women's Health, the same journal that published the findings from the 1998 meeting.

While the guidelines did not disclose financial conflicts of the eight authors, at least six are known to have worked for companies that make drugs used to treat PMDD, according to a MedPage Today/Journal Sentinel analysis of other published work by the authors.

One was Endicott, the Columbia University psychologist who led the 1998 meeting. She worked as a consultant and speaker to drug companies going back years. In an interview, she said that has not biased her work.

"I've never felt dependent on them or that I had to please them," she said.

How Many Women?

Independent experts say that while some women indeed suffer from severe premenstrual symptoms, it is doubtful that PMDD affects 6 million women in the United States, as is claimed.

Where did that number come from?

Meir Steiner, MD, PhD, of McMaster University in Toronto, was one of the researchers who took part in the 1998 meeting in Washington, D.C. Steiner worked as a speaker or consultant to several PMDD drugmakers, including Eli Lilly, Pfizer, and GlaxoSmithKline.

When it comes to PMDD specifically, estimates say as many as 8% of premenopausal women have it, but independent researchers say those calculations rely on shoddy data.

According to the DSM, which recognized PMDD as a disorder in 2013, the condition is defined as having at least 5 of 11 symptoms, which include feeling angry, irritable, depressed, or anxious, and having mood swings.

Sarah Gehlert, PhD, of the Institute of Public Health at Washington University in St. Louis, said she was suspicious that the various estimates were not following the definition from the manual.

"If it existed, we wanted it to be recognized," she said. "On the other hand, we didn't want to glorify something that didn't exist."

Gehlert's team studied 1,247 women from rural and urban communities in Illinois and Missouri and followed them through two menstrual cycles to determine if they met the criteria.

The finding: Only 1.3% of premenopausal women have PMDD.

That means just under 1 million women in the United States, not 6 million.

"We did become convinced that some women had PMDD," Gehlert said, "but we could also see that it had the potential to harm women if it became a quick-and-dirty diagnosis."

While the FDA approved Sarafem for the not-yet-existent diagnosis of PMDD in 2000, European regulators were more cautious.

In withholding approval, the European Medicines Agency cited concerns that women with less severe symptoms might be wrongly diagnosed and treated with a potent antidepressant. The drug has never been on the European market.

"The pharma industry went out trying to promote the condition so that more women self-presented with this disorder and consequently, put pressure on doctors to prescribe medications for them," said Saddichha Sahoo, MD, a psychiatrist at Ipswich Hospital in Brisbane, Australia, who wrote a 2010 paper about disease mongering in psychiatry, which included PMDD.

Indeed, early television ads for Sarafem showed a woman angrily trying to claim a shopping cart at the grocery store. The ad described symptoms of premenstrual symptoms and urged women to "Think again: it could be PMDD."

Experts Disagree

The ads flourished at a time when there was considerable uncertainty about what PMDD really was and how best to treat it.

In the years leading up to the approval of Sarafem, there was strong disagreement among mental health experts, ranging from those who wanted it removed from the diagnostic manual altogether to those who argued for moving it into the main section as an official mood disorder.

In the late 1990s, Eli Lilly brought Nada Stotland, MD, a prominent psychiatrist and women's health expert, to its headquarters in Indianapolis. Stotland strongly opposed FDA approval of Sarafem as well as the idea of establishing PMDD as a mental disorder.

Stotland said she felt the company was hoping it could get her to change her mind.

She recalled company officials argued that by getting the drug approved, it could help destigmatize the disorder. But, in an interview, Stotland said she wasn't buying it -- then or now.

She said she feared making the condition a mental disorder would lead to women with problems such as stress or depression getting lumped into a diagnosis of PMDD.

What's more, since Prozac was merely repackaged and renamed for PMDD, she felt it would make it easier for family practice doctors and gynecologists to prescribe it without doing the kind of psychological assessment that was need to rule out other mental problems.

Another concern was that having it in the diagnostic manual could help mask what otherwise might be a woman's justified reaction to abuse and mistreatment.

Stotland, who served as president of the APA from 2008 to 2009, said she fought its inclusion in the manual throughout her career.

"I gave up, essentially, after DSM-5," Stotland said of the latest edition of the manual.

A spokeswoman for the APA said the decision to include PMDD in its most recent diagnostic manual went through several layers of review. She noted committee members were not allowed to have received more than $10,000 in payments from drug companies in the previous year.

Psychiatrist Kimberly Yonkers, MD, a professor of psychiatry at Yale School of Medicine and a member of the broader task force that oversaw the change, said members "were aware of prior controversies" but "relied on scientific findings as guiding principles."

Dangerous Drugs

All antidepressants used to treat PMDD -- Sarafem, Zoloft, and Paxil -- carry the FDA's most stringent black box warning for increased risk of suicidal thinking.

The drugs also carry a substantially increased risk of causing lack of energy, sleepiness, and decreased libido.

While studies showed antidepressants worked in about 60% of women with PMDD, one clinical trial found basic calcium supplements were effective in 55% of women with premenstrual symptoms.

No rigorous studies have been done that show the long-term effectiveness of the antidepressants.

In practice, they seem to wear off after about 6 months, according to Amanda LaFleur, executive director of the National Association for Premenstrual Dysphoric Disorder.

Meanwhile, she said, for many women the only other approved drug, Yaz, only made symptoms worse.

In two clinical trials, Yaz reduced PMDD symptoms, but not a lot more than a placebo.

Women who took Yaz showed a 37.5-point improvement on a symptom scale that had a maximum of 126 points, but those who get a placebo had a 30-point improvement.

And the drug's effectiveness beyond three menstrual cycles is not known.

LaFleur said she started her association in 2013 to help women sift through all of their options.

For her part, she suffered from severe premenstrual symptoms since the age of 14, but found the drugs to be ineffective. Two years ago, at age 35, she took a more extreme route -- removal of her ovaries.

"Now, I have no symptoms whatsoever," she said.

Treating PMDD with birth control pills, such as Yaz, that include the drug drospirenone is especially concerning, said Diana Zuckerman, PhD, president of of the National Center for Health Research, a nonprofit think tank that analyzes health research.

The drug's label warns that women over 35 who smoke should not use Yaz, because of the risk of clots and the increased likelihood of a serious cardiovascular event.

"Safer drugs are available to effectively treat PMDD," Zuckerman said. "How bad is your PMDD that you are willing to put your life at risk?"

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